The key goal of this proposal is to identify the molecular mechanisms associated in maintaining 'white'and 'brite'phenotype of human adipocytes, with consequences for the regulation of fatty acid (FA)-induced insulin resistance in obesity and type 2-diabetes. Identification and characterization of a third type of adipocytes known as 'brite'(brown-in-white) or 'beige'or 'brown-like'adipocytes has drawn considerable attention, as these cells are thought to regulate energy. Remarkably, the white adipocytes can adopt the characteristics of brite adipocytes by various stimuli, but the mechanism(s) are not fully understood. In fact, UCP1 and CIDEA are most prominent markers for browning or britening, yet the mechanism of action of CIDEA in brown adipocytes or during the britening process remains elusive. We and others previously identified members of CIDE proteins, FSP27 (also called CIDEC) and CIDEA, to be lipid droplet associated proteins playing a role in fat metabolism. FSP27 is highly expressed in white adipocytes, whereas CIDEA is predominant in brown. Our preliminary data shows that a) FSP27 negatively regulates lipolysis, b) interacts with ATGL/Desnutrin, a rate-limiting enzyme for catalyzing the first step of hydrolysis of triglycerides, and c) FSP27 knockdown enhance fatty acid oxidation in adipose tissue, and d) CIDEA knockdown suppresses TZD- induced britening in human white adipocytes. CIDEA interacts with FSP27 in adipocytes, and also localizes in the nucleus where it interacts with liver-X-receptor (LXR) to increase FA oxidation in adipocytes. Therefore, we hypothesize that FSP27 and CIDEA play a critical role in the regulation of 'white'and 'brite'phenotype, respectively, by regulating ATGL-mediated lipolysis and/or nuclear factors, thus maintaining an energy balance that is essential for the physiological function of fat storage and thermogenesis in human adipose tissue. The proposed work will define the mechanism of action of FSP27 and CIDEA in energy storage and expenditure by regulating white vs brite phenotype in human adipocytes, and might provide new targets for the development of therapies to decrease the risk of obesity and related metabolic diseases.

Public Health Relevance

White adipocytes store energy as triglycerides, while brown adipocytes dissipate energy as heat and are required for non-shivering thermoregulation. In the last few years, a third type of adipocytes was identified, termed as 'brite'(brown-in-white) or beige, which might provide a new means of decreasing obesity associated circulatory fatty acids (FAs) by increasing energy expenditure. The pathway(s) regulating 'white'or 'brite'phenotype, however, are not fully understood. Therefore, the goal of this proposal is to identify the molecular mechanisms associated in maintaining 'white'and 'brite'phenotype of human adipocytes, with consequences for the regulation of FA-induced insulin resistance in obesity and type 2-diabetes.